Review Contribution of the Type II Chaperonin, TRiC/CCT, to Oncogenesis Soung-Hun Roh 1,:, Moses Kasembeli 2,:, Deenadayalan Bakthavatsalam 3, Wah Chiu 1 and David J. Tweardy 2,* Received: 21 September 2015 ; Accepted: 26 October 2015 ; Published: 6 November 2015 Academic Editor: Salvador Ventura 1 Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA; [email protected] (S.-H.R.); [email protected] (W.C.) 2 Division of Internal Medicine, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; [email protected] 3 Department of Molecular Cardiology, Texas Heart Institute, Houston, TX 77030, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-713-792-6517; Fax: +1-713-792-3029 : These authors contributed equally to this work. Abstract: The folding of newly synthesized proteins and the maintenance of pre-existing proteins are essential in sustaining a living cell. A network of molecular chaperones tightly guides the folding, intracellular localization, and proteolytic turnover of proteins. Many of the key regulators of cell growth and differentiation have been identified as clients of molecular chaperones, which implies that chaperones are potential mediators of oncogenesis. In this review, we briefly provide an overview of the role of chaperones, including HSP70 and HSP90, in cancer. We further summarize and highlight the emerging the role of chaperonin TRiC (T-complex protein-1 ring complex, also known as CCT) in the development and progression of cancer mediated through its critical interactions with oncogenic clients that modulate growth deregulation, apoptosis, and genome instability in cancer cells. Elucidation of how TRiC modulates the folding and function of oncogenic clients will provide strategies for developing novel cancer therapies. Keywords: protein-folding; proteostasis; oncogenesis; chaperone; chaperonin; HSP70/90; TRiC/CCT; oncoprotein 1. Molecular Chaperones and Oncogenesis Molecular chaperones constitute a major arm of the proteostasis network (Figure1); they play a central role in the maintenance of protein homeostasis through an intricate system of cooperative mechanisms that balance protein biosynthesis, folding, translocation, assembly/disassembly, and clearance [1,2]. Molecular chaperones are a diverse group of proteins that interact with and assist other proteins to properly attain functional conformation [3]. They can be classified into two mechanistic classes—chaperones that promote folding of non-native proteins by binding to and releasing their substrates into the bulk matrix of the cell and chaperones that promote folding by sequestering single protein molecules within a molecular cage (chaperonins). The former include most heat shock proteins (HSPs) whose expression is known to be up regulated in response to environmental stress, most prominently, HSP70 and HSP90. The eukaryotic chaperonin family includes the type I chaperonin, HSP60, and the type II hetero-oligomeric chaperonin, TRiC (T-complex protein-1 ring complex, also known as CCT). Chaperones often function as large protein complexes that include other proteins called co-chaperones. They are essential for cell survival as they protect against proteotoxic stress that may lead to protein misfolding and aggregation. The primary Int. J. Mol. Sci. 2015, 16, 26706–26720; doi:10.3390/ijms161125975 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2015, 16, 26706–26720 Int. J. Mol. Sci. 2015, 16, page–page actiontransiently of chaperones bind to hydrophobic is to transiently regions bind of to hydrophobicnascent or stress regions denatured of nascent proteins or stress and denatured prevent proteinsaggregation and during prevent the aggregation folding process during [4]. the folding process [4]. Figure 1. Model of the chaperone network involving HSP70, HSP90, and TRiC (T-complex protein-1 Figure 1. Model of the chaperone network involving HSP70, HSP90, and TRiC (T-complex protein-1 ring complex, also known as CCT). Newly synthesized nascent polypeptide chain interacts with the ring complex, also known as CCT). Newly synthesized nascent polypeptide chain interacts with the HSP70 family, which mediates folding either co-translationally or post-translationally. HSP70 also HSP70 family, which mediates folding either co-translationally or post-translationally. HSP70 also can can deliver a folding-intermediate to downstream chaperones HSP90 or TRiC/CCT to complete deliver a folding-intermediate to downstream chaperones HSP90 or TRiC/CCT to complete folding. folding. Increased proteinprotein chaperonechaperone capacitycapacity hashas beenbeen linkedlinked to the etiology of many diseases including cancer [[5].5]. Considerable evidence now exists im implicatingplicating molecular chaperones in the development of cancer; they have been shown to play a fundamental role in the molecular mechanisms that lead to thethe emergenceemergence andand progressionprogression ofof thethe tumortumor phenotype.phenotype. Accordingly, levelslevels of heat-shockheat-shock factor 1 (HSF1), a a transcriptional transcriptional regulator regulator of ofprotein protein homeostasis homeostasis that that activates activates the transcription the transcription of HSPs of HSPsmost mostimportantly importantly HSP70 HSP70 and HSP90, andHSP90, has been has shown been to shown be elevated to be in elevated many cancer in many cell cancer lines and cell tumors lines and [6]. tumorsIndeed, [the6]. Indeed,expression the of expression several HSPs of several is increased HSPs isin increased many tumors, in many such tumors, that HSPs such are that prognostic HSPs are prognosticbiomarkers biomarkers in cancer and in cancertheir overexpression and their overexpression is linked to ispoor linked survival to poor and survival response and to responsetherapy [7]. to therapyThe sensitivity [7]. The of sensitivity a wide variety of a of wide tumors variety to inhi of tumorsbitors of to HSP90 inhibitors and HSP70 of HSP90 exemplifies and HSP70 the exemplifiesimportance theof molecular importance chaperones of molecular in maintaining chaperones survival in maintaining of cancer survival cells [8,9]. of cancer cells [8,9]. The contribution contribution of ofTRiC TRiC to cancer to cancer has not has received not received as muchas attention much as attention members as of membersHSPs [5,7,9]; of HSPshowever, [5,7 ,9evidence]; however, is now evidence emerging is now implicating emerging implicating TRiC in the TRiC pathogenesis in the pathogenesis of numerous of numerous cancers. cancers.Importantly, Importantly, several proteins several proteins associated associated with tumorigenesis with tumorigenesis have been have identified been identified as bona as fidebona TRiC fide TRiCclients; clients; these include these include signal transducer signal transducer and activa andtor activator transcription transcription (STAT3), (STAT3), cyclins B cyclins and E, B P53 and and E, P53Von andHippel-Lindau Von Hippel-Lindau [10–14]. [10–14]. A recent study suggested that TRiC subunits, CCT2 and CCT1, are essential for survival and proliferation of of breast breast cancer cancer [15]. [15 ].CCT1 CCT1 was was shown shown to be to transcriptionally be transcriptionally modulated modulated by the bydriver the driveroncogene, oncogene, phosphatidylinositide phosphatidylinositide 3-kinases 3-kinases (PI3K). (PI3K).Whether Whether these observations these observations reflect the reflect protein the proteinfolding foldingfunction function of TRiC of complex TRiC complex or a non-chaperoning or a non-chaperoning role of roleindividual of individual subunits subunits is not isclear; not clear;however, however, individual individual subuni subunitsts of TRiC of have TRiC been have shown been shown to have to protein-folding have protein-folding capacity capacity [16]. While [16]. Whilehigher higherexpression expression levels of levels TRiC of have TRiC been have associat beened associated with tumorigenesis, with tumorigenesis, a recent analysis a recent of analysis cancer ofcell cancer lines appeared cell lines to appeared show less to correlation show less correlationbetween TRiC between concentrations TRiC concentrations and its specific and activity its specific The activitydisparity The between disparity TRiC between concentr TRiCations concentrations and TRiC activity and TRiC has activity been attributed has been attributedto the dynamic to the partitioning of substrates between TRiC, its co-chaperones, and HSPs that seems to be influenced by concentrations of HSP70 within the cell [8,17]. 26707 2 Int. J. Mol. Sci. 2015, 16, 26706–26720 dynamic partitioning of substrates between TRiC, its co-chaperones, and HSPs that seems to be influenced by concentrations of HSP70 within the cell [8,17]. 2. Role of Heat Shock Proteins (HSPs) in Oncogenic Signaling Chaperone support and maintenance of oncogenic signaling pathways is integral to the biology of malignant tumor initiation and growth. For example, HSP90’s activity is necessary for the conformational stability and activity of many kinases, transcription factors and hormones most of which are known oncogenes or closely linked to oncogenic signaling pathways [18–20]. The cytoprotective qualities of the protein folding network and its ability to adaptively respond to environmental cues have been co-opted in cancer. Chaperones are essential in supporting events that induce malignant cell transformation such as mutations or increased expression of oncogenic proteins and play a crucial